4. Report published by IARC in 2004, on the carcinogenic risk of areca nut & Betel quid (Tambula / Pan) chewing. Part-II

 

The International Agency for Research on Cancer (IARC) constituted a "working group" comprising 17 experts drawn from India, China/Taiwan, UK, USA, Germany, Netherlands and South Africa, to study the possible carcinogenic risk posed by areca nut and betel quid to humans. After a detailed study, the working group prepared a monograph having 300 pages, detailing the mode of the assessment and evaluation, the research papers considered for assessing each criterion, the type of research papers considered for the assessment etc. and was published in 2004 in Lyon, France.

The working group concluded the following in their monograph.

·    There is sufficient evidence in humans for the carcinogenicity of betel quid with tobacco. Betel quid with tobacco causes oral cancer and cancer of the pharynx and esophagus.

·    There is sufficient evidence in humans for the carcinogenicity of betel quid without tobacco. Betel quid without tobacco causes oral cancer.

·    There is sufficient evidence in experimental animals for the carcinogenicity of betel quid with and without tobacco.

·        There is sufficient evidence in experimental animals for the carcinogenicity of areca nut.

·      There is evidence suggesting lack of carcinogenicity in experimental animals for betel leaf and slaked lime.

·        There is limited evidence in experimental animals for the carcinogenicity of arecoline.

·        There is inadequate evidence in experimental animals for the carcinogenicity of arecaidine.

The working group concluded that areca nut causes oral submucous fibrosis, a precancerous condition in humans. Further it claims to have found sufficient evidence of carcinogenicity in experimental animals.

The overall conclusion was,

·        Betel quid with tobacco is carcinogenic to humans (Group 1).

·        Betel quid without tobacco is carcinogenic to humans (Group 1).

·        Areca nut is carcinogenic to humans (Group 1).

This monograph created a huge uproar against areca nut and its products among the cancer biologists, research community dealing with human health, doctors, policy makers and Government of several developed countries. This created a renewed interest in the research groups throughout the world to take up studies dealing with areca nut consumption and subsequent effect on human health.  

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3. Report published by IARC in 2004, on the carcinogenic risk of areca nut & Betel quid (Tambula / Pan) chewing. Part-I

 

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to World Health Organization (WHO) of the United Nations (UN) published its second report on areca nut / Tambula (betel quid/ Pan) in 2004 in the form of a monograph (Vol. 85). This monograph was an outcome of a one-year effort involving 17 member "working group" drawn from India, China/Taiwan, UK, USA, Germany, Netherlands and South Africa. Senior scientists from AIIMS New Delhi, TIFR Mumbai, Cancer Research Institute, Tata Memorial Centre Mumbai etc. were the working group members from India.

IARC claims that it will select the topic based on two criteria: (a) there is evidence of human exposure, and (b) there is some evidence or suspicion of carcinogenicity. As per IARC, a “carcinogen” is defined as any substance which is capable of increasing the incidence of malignant (cancerous) tumors upon human exposure. Based on these terms, IARC claims that there was sufficient evidence available to probe the carcinogenicity of areca nut & betel quid chewing in Human population.

As per IARC, Oral cancer is the leading type of malignancy in India and South-east Asia, whereas lung, breast, prostate and colorectum are the leading cancers in the Americas, Europe and Oceania. In South Central Asia, cancer of the oral cavity is the cancer with the highest incidence among the men and the third highest among women (after the cervix and breast). Large body of evidence arisen from studies in experimental animals and in-vitro studies (lab studies in petri plates) that investigated the effects of areca nut alone, as well as those of betel quid with or without tobacco during 1985 to 2003, provided an impetus for selecting areca nut / Tambula by the working group of IARC.

The working group considered the following in their study.

·        Exposure of general population to Tambula (with and without tobacco) and areca nut.

·        Research studies on oral cancer

·        Research studies on lesions and precancerous lesions and conditions

·        Studies on stomach, Liver and cervical cancer

·        Studies of cancer in experimental animals

·        Other data relevant to an evaluation of carcinogenicity and its mechanisms.

Note: To be continued in the next Part.

2. IARC report on the carcinogenicity of chewable tobacco & Betel quid (Tambula / Pan) in 1985

 

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to World Health Organization (WHO) of the United Nations (UN) published its first report on areca nut in 1985 in the for of a monograph (Vol. 37). This monograph was an outcome of a one-year effort involving 19 experts drawn from 10 countries (working group), 5 observers from 5 countries and 22 secretaries affiliated to IARC. After reviewing and analyzing numerous research papers published in reputed research journals, a week-long workshop at Lyon, France, the experts came out with a comprehensive report in the form of a monograph in 1985.

The working group looked into the carcinogenicity chewable tobacco, betel quid & areca nut in the consumers. The experts looked into the reports published on the evidence of carcinogenicity in experimental animals, DNA damage studies, Cell-line studies, case reports involving human subjects & epidemiological studies.

Based on these studies and a systematic evaluation, IARC came out with the following conclusions with respect to chewable tobacco, betel quid and areca nut as follows.

Chewable tobacco

1. There is sufficient evidence that oral use of chewable tobacco is carcinogenic to humans. 
2. There is sufficient evidence that oral use of tobacco mixed with lime (khaini) is carcinogenic to humans.

Betel quid (Pan / Tambula) comprising areca nut, betel leaf, slacked lime, catechu.

1. There is sufficient evidence that the habit of chewing betel quid containing tobacco is carcinogenic to humans.
2. There is inadequate evidence that the habit of chewing betel quid without tobacco is carcinogenic to humans.
3. The Working Group also concluded that, while there is sufficient evidence that the combined habits of smoking tobacco and chewing betel quid without tobacco cause oral and pharyngeal(throat) cancer.
4. There is limited evidence that areca nut with and without tobacco is carcinogenic to experimental animals.
5. The data are inadequate to allow an evaluation of the carcinogenicity of betel leaf or arecoline to experimental animals.

As per this monograph, neither areca nut nor the other constituents of betel quid / Tambula/ Pan (areca nut, betel leaf, Catechu and slacked lime) were implicated for carcinogenicity.  

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1. Prominent reports on carcinogenicity of Areca nut & Betel quid (Pan / Tambula)

 

More than 50 research papers were published during 1970 to 1980 on the link between Betel quid / Areca nut along with tobacco chewing and mouth & throat cancer. Many reports pointed out that the percentage of oral cancer among all cancers diagnosed in hospitals in Asia was always much higher than that usually found in western countries. In western countries, the habit of chewing betel quid, with or without tobacco, is virtually unknown. In many descriptive studies, investigators have obtained histories of chewing betel quid with tobacco from series of patients with oral cancer. In most of these studies, the percentage of patients who practice chewing habits is extremely large. Many research papers have revealed that a high incidence of oral, oro- and hypopharyngeal cancer is observed in regions of the world where a high proportion of the population practices betel-quid chewing. Out of the 2,67,000 new oral cancers estimated to occur in the year 2000 globally, 1,28,000 (48%) occur in South and South-East Asia. Out of 1,23,000 cases of oro- and hypopharyngeal (throat) cancer estimated to occur globally annually, 63 000 (51.2%) are accounted in South and South-Easts Asia as per an assessment by Ferley & coworkers of International Agency for Research on Cancer (IARC).

The International Agency for Research on Cancer (IARC) is an intergovernmental agency affiliated to World Health Organization (WHO) of the United Nations (UN). IARC has its own governing council, comprising 27 member countries including India as on today. Almost all the developed nations of the world are the members of the governing council of IARC.

IARC was stablished in 1965 by the World Health Assembly, as an autonomous agency of WHO with the aim of promoting international collaboration in cancer research. Its mission is to coordinate international studies on the causes of human cancer, the mechanisms of carcinogenesis and strategies for cancer prevention, with a particular focus on promoting research in regions of the world where it is lacking. As IARC is affiliated to WHO independent of any government, there is a belief that it provides a reliable and authoritative assessments of many facets of cancer information valued by scientists, governments, nongovernmental organizations and the general public, globally.

The evaluations of carcinogenic risk are made by international working groups of independent scientists. A detailed account of the procedures involved, research papers referred and methodology followed for analysing the data etc. are given in the monograph. Sufficient evidences are provided by IARC that complete transparency in the process of monograph preparation is followed. The monographs are prepared based on the examination of all relevant information (research papers published in reputed journals) in order to assess the strength of the available evidence that certain exposures could alter the incidence of cancer in humans. Based on thorough study, the agents/substances are classified as follows.

       i.         Group 1: The agent is carcinogenic to humans. Ex.: Lindane, soot, tobacco smoke, Benzene.

     ii.         Group 2A: The agent is probably carcinogenic to humans. Ex.: Malathion, Glyphosate (a popular weedicide).

   iii.         Group 2B: The agent is possibly carcinogenic to humans. Ex.: Chloroform Chlorophenoxy herbicides, DDT, Aloe vera whole leaf extract.

    iv.         Group 3: The agent is not classifiable as to its carcinogenicity to humans. Ex.: Ampicillin, Caffeine, Eugenol, Tea.

     v.          Group 4: The agent is probably not carcinogenic to humans.

So far, IARC has published four reports on the carcinogenicity of areca nut and its components, chewing of tobacco with or without betel quid (Tambula/Pan), with or without areca nut, as follows.

1.     Evaluation of the Carcinogenic risk of tobacco, Betel quid and areca nut chewing. Published in 1985, Vol. 37.

2.   Evaluation of carcinogenic risks to humans from betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. Published in 2004, Vol. 85.

3.  Evaluation of Carcinogenic Risks to Humans from Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines. Published in 2007, Vol. 89.

4.      Identification of carcinogenic hazards from arecoline. Published in 2021, Vol.128

A detailed commentary along with critical comments shall be provided on each report in my future Blogs.

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9. Alkaloids present in Areca nut - Part IV

 

In the last couple of Blogs, the arecoline & other alkaloid contents in the green immature areca nut studied in different countries was discussed. In this Blog, arecoline & other alkaloid content of the areca fruits of 9-10 month’s maturity is discussed.

Shivashankar et al., (1968) from CFTRI Mysore, had studied the chemical composition of Chali (White supari) purchased from important areca growing regions of Kerala and Karnataka over two years (1964 to 1966). They had used rudimentary methods available at that time to estimate arecoline content. They concluded that the arecoline content varies between 0.1 to 0.7 % in Chali on dry weight basis, collected from different areca growing regions of Karnataka and Kerala state of India. 

Wang et al., (1997), had studied the arecoline content of areca nuts of 9-10 months’ maturity collected from Taiwan. They had reported the arecoline content of 0.16% in the ripened fruit on fresh weight basis. Jantarat et al., (2013) had reported an arecoline content of 0.094 % in 8 months old, matured nuts on fresh weight basis. They had collected the areca nut sample from Nakhon Si Thammarat, Thailand.

Chavan and Singhal (2013) had analyzed the arecoline content of Chali purchased from the local market in Mumbai using HPLC method. They had reported an arecoline content of 1.279% (12.79 mg/g).  Jain et al., (2017), have done a comprehensive study of arecoline content in Chali and various areca nut products sold in the market in China and India. They had reported an arecoline content of 0.064 to 0.222 % (dry weight) using advance LC-MS/MS method. Arecoline content of 0.119% was the median value and 0.127% was the mean value in the Chali (white supari) collected from the bulk traded in the Mumbai market. The arecoline content found in the Gutka samples produced and sold in India were 0.074 & 0.116 %. The arecoline content in the Bing lang purchased from Hunan province China were in the range of 0.107 to 0.144%.  Levels of Guvacine ranged from 0.139 to 0.816% dry weight, accounting for more than 50% of the total alkaloid content in most of the products. The levels of Arecaidine and Guvacoline ranged from 0.014 % to 0.170 % and 0.017 % to 0.099 % dry weight, respectively.

In conclusion, about a dozen alkaloids have been identified so far in areca nuts and Arecoline is considered as a key biologically active alkaloid among them. Its concentration will be high in the early developmental stage and decreases with maturity. Areca nut cultivated in Taiwan, China, Indonesia and Darwin Island, Australia, reported arecoline content on higher side (0.3% and above) in the unripe green nuts. Whereas the unripe green areca nuts studied in Thailand and India had lower arecoline content (less than 0.3%). Lot of variation (up to 400%) in arecoline concentration was found in areca nuts cultivated in different regions.  The analysis of various areca nut samples sold in the market revealed that the arecoline content in them is in the range of 0.064 to 0.222 % (0.64 to 2.22 mg/g). In one instance, the arecoline content was found to be as high as 1.279% (12.79 mg/g) in Chali sample collected from Mumbai market, India.

References:

Shivashankar et al., (1968). Physical and chemical characteristics of processed areca nuts. Journal of Food Science & Technology, Vol.  6, pp. 113-116.

Wang et al., (1997), Contents of Phenolics and Alkaloids in Areca catechu Linn. During Maturation, Journal of Agriculture & Food Chemistry. Vol. 45, pp. 1185-1188

Jantarat et al., (2013), A Simple and Rapid HPLC Technique for Determination of Arecoline in Areca Nut (Areca catechu L.) Extract, Walailak Journal of Science & Technology, Vol. 10(1), pp. 57-66.

Chavan & Singhal (2013). Separation of polyphenols and arecoline from areca nut (Areca catechu L.) by solvent extraction, its antioxidant activity, and identification of polyphenols. Journal of  Science of  Food & Agriculture.  Vol. 93(10), pp. 2580–2589.

Jain et al (2017). Analysis of Alkaloids in Areca Nut-Containing Products by Liquid Chromatography−Tandem Mass Spectrometry. Journal of Agricultural and Food Chemistry, Vol. 65, pp. 1977−1983